American College of Gastroenterology 65th Annual Scientific Meeting Conference Summaries

Transcription

American College of Gastroenterology 65th Annual Scientific Meeting
Conference Summaries
American College of Gastroenterology 65th Annual
Scientific Meeting
(Valid for CME until November 2, 2001)
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If you cannot register online and complete the activity, you may also receive credit by
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Goal
The goal of these activities is to define "state-of-the-art" treatment protocols
and clinical strategies for the prevention, diagnosis, and management of
diseases of the gastrointestinal tract and liver, to enhance the care of individuals
with these diseases and support quality clinical practice of healthcare
professionals involved in their care.
http://www.medscape.com/medscape/cno/2000/ACG/PrintDay.cfm?conference_id=77&day_num=1 (1 of 41) [11/4/2000 12:26:45 AM]
Learning Objectives
These summaries are intended for physicians, nurses, and other healthcare
professionals conducting research and/or providing primary or specialty care
for individuals with diseases of the gastrointestinal tract and liver.
Upon completion of this self-study activity, participants will be able to:
1. Summarize the latest trends and topical issues in the fields of
gastroenterology and hepatology.
2. Evaluate new diagnostic or therapeutic strategies as they relate to specific
clinical entities, including inflammatory bowel disease, irritable bowel
syndrome, hepatitis C, and Barrett's esophagus/esophageal adenocarcinoma.
3. Define established and new forms of therapy for diseases of the
gastrointestinal tract and liver.
4. Discuss the latest advances in diagnostic and therapeutic endoscopy.
5. Define current concepts in the pathophysiology of diseases of the
gastrointestinal tract and liver as they influence the approach to clinical
management and affect clinical outcome.
6. Integrate information regarding the diagnosis, prognosis, treatment, and
pathophysiology of diseases of the gastrointestinal tract and liver to enhance
patient care and improve clinical outcomes.
Eligibility for Credit
Continuing education credit will be awarded to physicians, physician assistants, registered
nurses and nurse practitioners who successfully complete this activity as described in the
section Instructions for Credit. Certificate is defined as a record of participation. For
information on applicability and acceptance of continuing education credit for this activity,
please consult your professional licensing boards.
Instructions for Credit
Participation in this self-study activity should be completed approximately two (2.0) hours.
To successfully complete this activity and receive credit, participants must follow these
steps during the period from November 2, 2000 through November 2, 2001
1. Register for continuing education credit by completing the "registration" process.
2. Read the learning objectives.
3. Read the article text and tables, and figures.
4. Read, complete, and submit answers to the post test questions and evaluation
questions. Participants must receive a test score of at least 70%, and respond to all
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Table of Contents
●
CME Activity
Supplemental Summary Articles
(CME valid until November 2, 2001)
(not required for CME)
Inflammatory Bowel Disease Treatment:
Effectiveness, Safety, and Adherence
Bret A. Lashner, MD
●
New Developments in Endoscopy
Charles J. Lightdale, MD
●
New Insights Into Irritable Bowel
Syndrome
Kevin W. Olden, MD
●
Barrett's Esophagus: The Challenge
Continues
M. Brian Fennerty, MD
●
Chronic Hepatitis C
Rowen K. Zetterman, MD, FACP, FACG
Inflammatory Bowel Disease Treatment: Effectiveness,
Safety, and Adherence
Bret A. Lashner, MD
Introduction
Much has been learned in recent years about the use of old and new therapies for treating inflammatory
bowel disease (IBD). New therapies (eg, infliximab) and better monitoring of older drugs (eg,
6-mercaptopurine or azathioprine) have advanced our treatment options for this disease entity. The
annual meeting of the American College of Gastroenterology held in New York City from October
16-18, 2000, provided a forum for investigators to continue discussions on both their experiences and the
latest insights into therapy for IBD. A symposium conducted during this meeting concentrated on safety
and adherence issues regarding IBD therapy. The following report summarizes the key clinical findings
presented at that symposium and highlights important podium and poster presentations that further
contribute to a better understanding of the challenges facing the physician treating the patient with IBD.
Infliximab: Efficacy and Safety Issues
Stephen B. Hanauer, MD, from the University of Chicago, discussed the effectiveness and toxicity
experience with more than 60,000 infusions of infliximab (Remicade) given to patients with Crohn's
disease in the United States since the drug was approved for clinical use by the FDA in 1998. Infliximab
is a chimeric, monoclonal antibody directed against tumor necrosis factor-alpha (TNF-alpha) that
demonstrates a high specificity and affinity to TNF-alpha. Results of a number of studies have suggested
a central role for TNF-alpha in chronic intestinal inflammation.
In general, the effectiveness of infliximab in clinical practice has been comparable to that reported in the
clinical trials. Thus, a single infusion of infliximab (5 mg/kg) given to a patient with inflammatory-type
Crohn's disease can be expected to improve as many as 80% of patients and induce remission in
approximately one third of all patients. For fistulous Crohn's disease, 3 infusions given over 6 weeks can
be expected to decrease drainage in 70% and completely close fistulas in approximately 50% of cases.
Based on the University of Chicago experience with 203 patients with Crohn's disease, infliximab
appears to be steroid-sparing.
Investigators from Lenox Hill Hospital and Mount Sinai Hospital in New York, Brown University
School of Medicine, Beth Israel Deaconess Medical Center, and the Cleveland Clinic confirmed these
response rates in adults and children.[1-4] Additionally, Chey and colleagues[5] from the Rochester
Institute for Digestive Diseases and Sciences showed that infliximab was effective in 16 of 17 patients
treated for ulcerative colitis. Unfortunately, these remarkable findings seem to wane 12 weeks following
the last infusion. Whether repeated "maintenance" infliximab infusions or institution of high-dose
immunosuppressive therapy at the time of infusion will successfully maintain remission has yet to be
established.
Careful selection of patients for infliximab infusion should increase response rates and minimize cost and
toxicity by avoiding administration of the drug to patients less likely to respond. Brzezinski and
colleagues[4] from the Cleveland Clinic found that individuals who smoked cigarettes and those not on
immunosuppressive medications were less likely to respond to therapy with infliximab, especially
patients with inflammatory-type disease. By contrast, Rawlins and colleagues[6] from the Virginia Mason
Clinic failed to confirm a better treatment effect in patients taking azathioprine, 6-mercaptopurine, or
methotrexate. Rusche and colleagues[7] from the Indiana University Medical Center demonstrated a
better response rate to infliximab in patients with ileocolic or colonic Crohn's disease vs those with small
bowel disease.
The use of infliximab in the appropriate patient populations -- despite issues of cost -- can lead to good
savings overall for the healthcare system potentially by decreasing need for gastrointestinal surgery by
15%, the need for endoscopies by 34%, and emergency department visits by 63%.[8]
Adverse Events
Although clinical trials of infliximab report that up to 15% of patients developed human anti-chimeric
antibody (HACA), no differences in adverse effects among treated and placebo groups were found. The
rate of HACA-positivity may be diminished by concomitant administration of immunosuppressive
therapy. Adverse events were primarily acute, minor, and could be treated during infusion with
diphenhydramine or, alternatively, by slowing the rate of infusion. Fortunately, severe antibody-mediated
reactions such as asthma, hives, or anaphylaxis are very rare. It is unknown whether antibody-mediated
reactions are related to HACA, but it is reasonable to withhold infliximab infusions in patients who are
positive for the now commercially available HACA. Serious delayed hypersensitivity reactions, usually
characterized by arthritis at least 7 days after the infusion, can be observed in a minority of patients who
are reinfused more than 3 months after an initial infusion.
The importance of anti-TNF therapy in Crohn's disease was further underscored by Kim and colleagues[9]
from the Medical College of Wisconsin. These investigators found that thalidomide was effective in
patients who could not tolerate infliximab. What is the relevance of thalidomide in this setting?
Thalidomide, a teratogen that has recently shown efficacy in the treatment of leprosy, also has
anti-inflammatory effects. Another adverse effect associated with infliximab is the apparent development
of fibrous strictures in 9% (7/76) of patients within a median of 30 days after the inflammation is
successfully treated.[10]
Research is currently underway to expand the indications for infliximab in the IBD setting to include
ulcerative colitis, pyoderma gangrenosum, and ankylosing spondylitis.
6-Mercaptopurine and Azathioprine: The Utility of Metabolite
Monitoring
Background and Significance
Immunomodulating agents that suppress the immune system and thus downregulate inflammation, such
as 6-mercaptopurine (6-MP) and azathioprine (AZA), are important in the long-term treatment of IBD.
What is the rationale for the use of immunomodulators in this setting? The rationale stems from
observations implicating immunologic mechanisms in the pathogenesis of IBD.
Ernest G. Seidman, MD, from Sainte Justine Hospital in Montreal, presented the latest findings on the
clinical utility of measuring 6-MP and AZA metabolites in patients undergoing treatment for IBD. 6-MP
and AZA are now 2 of the most widely used drugs for IBD because of their efficacy in both inducing and
maintaining remission and their favorable adverse event profile. Data from 3 studies conducted by
investigators at Lenox Hill Hospital confirmed the safety of short- and long-term 6-MP (with the
exception of an increased risk of malignancy in patients with sustained leukopenia [WBC < 4000/mm3
for at least 3 weeks]).[11-13] Approximately 8% of patients on 6-MP or AZA will develop acute
pancreatitis and 1% will develop allergy characterized by fever, rash, and abdominal pain. About 10%
will develop leukopenia and thus need to have doses adjusted downward. 6-MP and AZA can take up to
3 months or longer to reach efficacy, creating a clinical dilemma in nonresponding patients.
Are patients who fail to respond being inadequately dosed or have they simply not taken the drug long
enough to have an opportunity to respond? In previous years, clinicians have escalated the dose until
mild leukopenia (WBC < 5,000/mm3) was induced. As compared to patients without leukopenia,
leukopenic patients were more likely to respond, more likely to have their dose of steroids reduced, and
more likely to be adequately treated for complications of IBD. However, this "crude" measure of drug
level is not an acceptable practice because not everyone who is dosed adequately will become
leukopenic, and toxic doses could be given before leukopenia develops.
Strategies for Monitoring Therapy
Technology is now available that allows for more accurate dosing of 6-MP and AZA. The technology
also offers clinicians the opportunity to find the very narrow window between efficacy and toxicity for
these medications. The end products of the metabolic pathways for these immunosuppressants and an
important metabolizing enzyme have become very useful in managing patients with IBD (see Figure).
Figure. The metabolic pathway of azathioprine and 6-mercaptopurine.
AZA is converted to 6-MP during the first pass of this drug through the liver. 6-MP is further
metabolized to 6-thioguanine (6-TG), the active metabolite that can be measured in blood. 6-TG levels
greater than 235 pmols/8x108 cells have been shown to correlate with response to 6-MP. Achkar and
colleagues[14] from the Cleveland Clinic Foundation proposed that 6-TG levels greater than 260
pmols/8x108 cells should be the preferred cutoff for therapeutic effectiveness. Moreover, these
investigators demonstrated that 6-TG levels were more strongly associated with response than either
immunosuppressant dose or WBC less than 5000/mm3.
6-MP is inactivated by 2 pathways: metabolism by xanthine oxidase and by thiopurine methyltransferase
(TPMT). Xanthine oxidase metabolizes 6-MP to the inactive thiouric acid. Patients on allopurinol, a
xanthine oxidase inhibitor, should be given immunosuppressants with caution, probably at very low
doses. Measuring 6-TG levels would be extremely helpful in such patients. Milk contains xanthine
oxidase and patients whose 6-TG levels are low despite relatively high doses of the medication should be
advised to minimize milk consumption. 6-MP is also metabolized to the inactive
6-methylmercaptopurine (6-MMP) by TPMT. 6-MMP levels greater than 5700 pmol/8x108 cells have
been associated with hepatotoxicity, but transient hypertransaminasemia is seen only in a minority of
patients. Immunosuppressive medications need not be discontinued if patients are found to have very
high levels of 6-MMP and normal liver function tests, but careful monitoring of liver function is
essential.
Dubinski and colleagues[15] from Cedars-Sinai Medical Center presented their work on 6-TG in the
treatment of patients with active Crohn's disease who are found to have very high levels of 6-MMP.
These patients have an abnormal metabolism of 6-MP such that too much of the inactive 6-MMP is
produced and insufficient 6-TG is produced in order to have a therapeutic effect. Providing 6-TG directly
to 9 patients with IBD (6 with Crohn's disease and 3 with ulcerative colitis), Dubinski showed a response
in 7 and remission in 6. One patient developed leukopenia and none developed or had recurrence of
hepatotoxicity. Alternatively, TPMT activity can be diminished when 5-aminosalicylic acid (5-ASA)
products are administered. Markowitz and colleagues[16] from the North Shore-Long Island Jewish
Health System showed that 2 patients with high 6-MMP and low 6-TG could have their metabolite
profile improved by coadministering 5-ASA.
Metabolite levels need not be checked in every patient. There are 2 populations, however, for which
monitoring metabolite levels could prove extremely important in improving patient care and outcome: 1)
Metabolite levels should be checked in patients who fail to respond to immunosuppressive therapy to
distinguish the true nonresponders from those who are inadequately dosed and from patients who are not
adherent to their medication regimens. Therapy can be changed or abandoned based on the results. 2)
Monitoring metabolite levels would be helpful for patients whose remission is being maintained by 6-MP
or AZA. The chances of remission being maintained are likely to be greatest when 6-TG levels are within
the therapeutic range.
Studies for determining levels of TPMT are also available commercially. TPMT is absent in 1 in 300
individuals and, because of the risk of severe toxicity, immunosuppressive therapy should be avoided in
them. Eleven percent of the population has lower-than-normal levels and should therefore have
immunosuppressants administered at doses lower than what would be given normally. TPMT levels
should be checked in all patients being considered for administration of high-dose oral (6-MP 1.5
mg/kg/day or AZA 2.5 mg/kg/day) or intravenous immunosuppressive therapy. Mahadevan and
colleagues[17] from the Mayo Clinic showed that intravenous AZA given to 9 patients with severely
active ulcerative colitis enabled 5 of these patients to avoid colectomy and 3 to achieve remission. All
such patients should have TPMT levels measured prior to administration of intravenous AZA.
Pregnancy and Nursing: Safety of Commonly Used IBD Drugs
Bret A. Lashner, MD, from the Cleveland Clinic, discussed the available information on the safety of
IBD medications in pregnant women. There is a scarcity of controlled trials in pregnant patients with
IBD because of the potential liability associated with this population. Moskovitz and colleagues[18] from
the Mount Sinai School of Medicine in New York reported on 231 pregnancies among 120 patients with
IBD. In these pregnancies, there was a 6% occurrence of prematurity, a 21% occurrence of spontaneous
abortion, and a 2.6% occurrence of major birth defects; medications were not associated with a poor
outcome.
What Do We Know?
There are no IBD drugs listed as Category A (controlled studies in women fail to show a fetal risk). Still,
it is generally believed that corticosteroids and all 5-ASA products are safe and should be used if
necessary in pregnant women. Steroids are considered Category C drugs (fetal risk unknown; ie, either
definite fetal risk in laboratory animals has been shown and no studies in women are available, or no
studies in animals or women have been done) and 5-ASA products are considered Category B drugs
(some fetal risk in laboratory animals has been demonstrated but either no risk has been found in
controlled trials in women or no studies are available). Potentially, sulfasalazine, being a sulfa drug that
crosses the placenta and is passed in breast milk, could displace bilirubin from albumin, thereby putting
the baby at an increased risk for kernicterus. Fortunately, kernicterus has never been observed in babies
of mothers on sulfasalazine and, for this reason, it therefore need not be avoided. Sulfasalazine does,
however, competitively inhibit folic acid absorption, and pregnant women on sulfasalazine thus need to
be supplemented with folic acid to minimize the risk of neural tube defects. Topical 5-ASA has been
shown to be safe during pregnancy.
Considerable controversy exists concerning the use of 6-MP or AZA. Both are listed as Category D
drugs, meaning that there is a definite risk to the fetus. Therefore, these agents should only be used if the
risk of not treating the mother with these medications outweighs the risk to the fetus. These drugs
interfere with purine biosynthesis and are especially toxic to rapidly dividing cells. In laboratory animals,
6-MP and AZA are associated with cleft palate, limb malformations, and ocular abnormalities. In women
on these immunosuppressants for organ transplantation or systemic lupus erythematosus, there appears to
be no increased risk of congenital abnormalities -- but there is a risk for growth retardation and
prematurity. In IBD patients, there are few case series that document prematurity and spontaneous
abortions in women who were taking 6-MP and AZA and congenital abnormalities when fathers were
taking 6-MP. However, the number of patients in these studies is small and the number of complications
observed is exceedingly small as well. Dr. Lashner recommended that, if at all possible, women be
switched from 6-MP or AZA to steroids and 5-ASA agents during their pregnancy and then be switched
back after delivery.
There is so little information on infliximab in pregnancy that it is listed as a Category C drug.
Cyclosporine also is listed as a Category C drug, despite the fact that there is some risk in laboratory
animals; there are no studies in women. Metronidazole (Category C) is teratogenic in animals, especially
in the first trimester, and should therefore be avoided early in pregnancy. Methotrexate is listed as
Category X due to teratogenicity and the general consensus that the risks to the fetus outweigh any
benefits to the mother; this drug must be avoided during pregnancy and breastfeeding.
Conclusions: What Should and Shouldn't Be Used to Treat the Pregnant Patient With
IBD?
In summary, all 5-ASA products and corticosteroids appear to be safe during pregnancy and nursing.
Methotrexate is contraindicated, and all other drugs should be used only if the benefits to the mother
outweigh any possible risk to the fetus.
Adherence to Recommended IBD Therapy
Sunanda V. Kane, MD, from the University of Chicago, continued the trend with a discussion on
strategies for improving patient adherence to recommended therapy. "Adherence" is a preferable term to
"compliance" because the former implies a reciprocal interaction between patient and physician.
Adherence can be defined as the extent to which patient behavior coincides with medical advice. In most
chronic diseases, including IBD, nonadherence ranges between 25% and 50%. Fully 40% of ulcerative
colitis patients do not take sulfasalazine as prescribed. There are many reasons for nonadherence,
including too-frequent dosing regimens, excessive medication expense, adverse drug effects, and failure
to realize the importance of maintenance therapy (including cancer surveillance colonoscopy) for patients
who feel well.
The key to improving adherence to therapy centers on patient education by medical professionals. Fully
one third of IBD patients feel the need to seek alternative medical therapy (eg, acupuncture, herbal and
nutritional supplements, massage, yoga, meditation). [19] Hilsden and colleagues from the University of
Calgary reported that alternative medicine advice is often freely dispensed to IBD patients by health food
store employees, herbalists, and chiropractors. [20] The more the patient is aware of the nuances of IBD
and its sequelae, as learned from discussions with his or her physician, the more likely that patient will
adhere to therapeutic recommendations.
Also, simplifying oral regimens to twice daily, choosing less expensive medications, insisting on
follow-up clinic visits, and encouraging attendance at health talks or support groups are strategies likely
to improve adherence. Monitoring prescription refills and drug metabolite levels may be useful,
especially in patients who are not responding as expected to therapy.
Conclusions and Implications for Clinical Practice
We have entered a new era in the therapy of IBD. The success of new drugs such as the biologic agent
infliximab has driven the pharmaceutical industry to investigate other strategies for interrupting the
unchecked inflammatory process that underlies the disease. Drug development in IBD has not yet peaked
-- there is much more on the way. Additionally, with immunosuppressive metabolite monitoring we can
now better dose patients and follow adherence than we ever could in the recent past. Very directly, new
ideas have led to better therapy. And, as our experience has grown, use of potentially toxic agents in
pregnancy and nursing has become less uncertain than it once was.
Overall, data presented at the annual meeting of the American College of Gastroenterology show that as
our therapeutic options and experience continue to expand, we are significantly improving the care of the
patient with IBD.
References
1. Chusid BG, Blank A, Kaganovskaya M, Korelitz BI. Intravenous Remicade outpatient treatment
of Crohn's disease: a personal experience [abstract]. Am J Gastroenterol. 2000;95:2531.
2. Pittman N, Birnbaum A, Benkov K. Anti-tumor necrosis antibody in children with Crohn's disease
[abstract]. Am J Gastroenterol. 2000;95:2505.
3. Shah SA, Fefferman DS, Farrell RJ, et al. Efficacy and safety of infliximab in 221 Crohn's disease
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patients [abstract]. Am J Gastroenterol. 2000;95:2640-2641.
Parsi M, Richardson S, Achkar J-P, et al. Non-smoking and concurrent immunosuppressive use are
predictors of response to infliximab in patients with Crohn's disease [abstract]. Am J
Gastroenterol. 2000;95:2499.
Chey WY, Hussain A, Ryan C, et al. Infliximab is an effective therapeutic agent for ulcerative
colitis [abstract]. Am J Gastroenterol. 2000;95:2530-2531.
Rawlins M, Gelfand MD, Kozarek RA, et al. Does coadministration of immunosuppressive agents
alter response to infliximab in Crohn's disease [abstract]? Am J Gastroenterol. 2000;95:2548-2549.
Rusche M, Helper D, Rex D, et al. Factors influencing the efficacy of infliximab in the
management of Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2500.
Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource utilization in patients with
Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2499-500.
Kim JP, Emmons JE, Ginion DG. History of previous infliximab response predicts thalidomide
efficacy in refractory Crohn's patients [abstract]. Am J Gastroenterol. 2000;95:2532.
Vasilopoulos S, Kugathasan S, Saeian K, et al. Intestinal strictures complicating initially
successful infliximab treatment for luminal Crohn's disease [abstract]. Am J Gastroenterol.
2000;95:2503.
Lobel EZ, Xuereb MA, Panagopoulos G, et al. Optimal duration of treatment with
6-mercaptopurine for ulcerative colitis [abstract]. Am J Gastroenterol. 2000;95:2541.
Korelitz BI, Warman JI, Fleisher MR, et al. Short and long term toxicity to 6-mercaptopurine in
the treatment of Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2539.
Rajapakse R, Furr S, Jaramillo-Nieves L, et al. Is there a predisposition to malignancy when
leukopenia is sustained during 6-mercaptopurine treatment of inflammatory bowel disease
[abstract]? Am J Gastroenterol. 2000;95:2548.
Achkar J-P, Stevens T, Brzezinski A, et al. 6-Thioguanine levels versus white blood cell counts in
guiding 6-mercaptopurine and azathioprine therapy [abstract]. Am J Gastroenterol. 2000;95:2291.
Dubinski M, Hassard PO, Kam L, et al. An open label pilot study evaluating the safety, tolerance
and efficacy of thioguanine as an alternate therapy in patients failing 6-mercaptopurine [abstract].
Am J Gastroenterol. 2000;95:2532.
Markowitz JF, Daum F. Inhibiting thiopurine methyltransferase (TPMT) activity with mesalamine
improves therapeutic 6-mercaptopurine metabolites in children with Crohn's disease [abstract]. Am
J Gastroenterol. 2000;95:2542-2543.
Mahadevan U, Tremaine WJ, Johnson T, et al. Intravenous azathioprine in severe ulcerative
colitis: a pilot study [abstract]. Am J Gastroenterol. 2000;95:2542.
Moskovitz D, Scherle E, Chapman ML, et al. 5-ASA, metronidazole, ciprofloxacin, prednisone,
6-mercaptopurine and azathioprine use in pregnant patients with inflammatory bowel disease
Borum M, Johnson M, Farmer R, Chutkan R. The use of alternative medicine practices amongst
patients with inflammatory bowel disease [abstract]. Am J Gastroenterol. 2000;95:2493.
Hilsden RJ, Verhoef MJ, Rapshuk I, et al. What treatments are recommended by complementary
medicine providers for inflammatory bowel disease and what are their views on the efficacy and
safety of there therapies [abstract]? Am J Gastroenterol. 2000;95:2495.
New Developments in Endoscopy
Charles J. Lightdale, MD
Introduction
The enormous impact of endoscopy on the practice of gastroenterology was highlighted in 2 major
clinical symposia held at this year's Annual Meeting of the American College of Gastroenterology. The
first of these programs focused on updates of currently available, yet evolving, endoscopic methods.
Concordant with the shift of endoscopy from a strictly diagnostic method to one that includes minimally
invasive therapies, 4 of the 5 presentations related to therapeutic endoscopy. The initial focus was on new
endoscopic treatments for gastroesophageal reflux disease (GERD), followed by discussions on
endoscopic mucosal resection and mucosal ablation using photodynamic therapy and argon plasma
coagulation. The session closed with an update on strategies in endoscopic ultrasonography.
Endoscopic Antireflux Procedures
Endoscopic Gastroplasty
The concept of treating GERD using an endoscopic per-oral method burst into prominence this year with
the simultaneous approval by the United States Food and Drug Administration (FDA) of 2 new methods
for this purpose. These endoscopic therapies were presented in detail by Dr. Steven A. Edmundowicz of
Washington University Medical School in St. Louis, Missouri.
The first of the antireflux endoscopic procedures discussed uses an endoscopic "sewing machine" to
place sutures in the region of the lower esophageal sphincter (LES) and gastric cardia. The sewing
machine involves suction and a needle device to carry a suture through the muscularis propria. The
suture is drawn to the outside where a surgical knot is tied. The knot is then pushed down alongside the
endoscope using a special knot-pusher device to leave a fixed fold in the wall of the esophago-gastric
junction or cardia. The crimped fold narrows and stiffens the area, leading to decreased reflux. Mastery
of the technique will clearly require a high level of endoscopic skill, experience, and training with the
new instruments.
Dr. Edmundowicz reviewed the 2 main studies carried out thus far that employed endoscopic sewing for
treating gastroesophageal reflux. A multicenter trial involving 64 patients showed a reduction in
heartburn score from a baseline of 22.8 to 9.2 at 3 months following the procedure (P < .001). Similarly,
regurgitation score was reduced from a baseline of 1.8 to 0.6 at 3 months (P < .001).[1]
In the second trial carried out by the sewing machine's developer, Dr. Paul Swain, London, England, 102
patients with GERD were treated with endoscopic gastroplasty. The baseline symptom score of 5 was
reduced to 1 at 3 months (P< .05). The length of the LES was increased from 2 cm to 3 cm and the LES
pressure increased from 5 mmHg to 8 mmHg (P < .05). The time of esophageal pH recordings < 4 was
reduced from 8.4% to 2.7% (P < .05).[2]
Complications of the sewing procedures were at an acceptable rate. In the first study, there was 1 small
perforation and 2 minor overtube injuries. In the second study, there was 1 perforation and dysphagia
occurred transiently in 3 patients.
Radiofrequency Energy
In this procedure, multiple foci of radiofrequency energy are delivered to the muscle layer of the
esophago-gastric junction and gastric cardia. The technique is carried out with a Stretta device, which
employs a balloon from which rows of needles are passed into the area to be treated. Radiofrequency
energy is produced at the needle tips using a processor that controls the rate and degree of the resultant
injury. The mucosa is simultaneously cooled with infused water to avoid mucosal effect.
An initial multicenter clinical study of the Stretta procedure was performed in 28 patients and resulted in
no complications. The need for antacid medication was decreased from a baseline of 100% to 21% at 6
months. The time at esophageal pH < 4 was decreased from 12% to 6.7% (P < .05), heartburn score was
decreased from 3.7 to 1.4 (P < .001), and a GERD quality-of-life score was reduced from 24.4 to 7.9 (P <
.001).[3]
Injection
There have been several pilot experiments conducted on the endoscopic injection of bland or inert
materials into the area of the LES in an attempt to narrow the area and increase sphincter pressure. This
method has the appeal of being technically simple, potentially less expensive, and relatively easy to carry
out for most gastrointestinal endoscopists. Concerns center around long-term risks and potential
migration or reactions over time. Clinical trials have not been reported.
Implications
There is a great deal still to be learned following the early success of endoscopic suturing and
radiofrequency treatment for GERD. The best placement of endoscopic sutures has yet to be determined,
and outcome differed in the 2 studies presented so far. The mechanism of action of the Stretta procedure
has not been fully elucidated. Possibilities include a stiffening effect, which overcomes the distension of
the LES that occurs with a meal, or an effect on afferent nerve reflexes at the gastroesophageal junction.
Patient selection may be critical in terms of when and how to carry out these endoscopic antireflux
procedures. In any case, there is no doubt that the dramatic introduction of these procedures this year will
begin to alter the management of patients with GERD. Pharmacologic therapy, primarily with proton
pump inhibitors, and laparoscopic fundoplication have both been highly effective, but each can be
unsatisfactory at times. The endoscopic procedures are very new compared with standard medical and
surgical therapies, but they do have the potential to be equally effective, less expensive, and less
invasive.
Endoscopic Mucosal Resection
Endoscopic mucosal resection (EMR) is a technique that was developed and popularized in Japan and
has now attracted wide attention among American gastrointestinal endoscopists. In Japan, the method has
been primarily used for early gastric cancer -- which is not a common problem in the United States.
However, EMR seems to be a highly safe and effective method with broad applicability for minimally
invasive removal of lesions confined to the mucosa throughout the gastrointestinal tract.[4]
Dr. Gregory G. Ginsberg, from the University of Pennsylvania Medical Center, discussed the EMR
technique. The key element of this procedure involves lifting the mucosal layer away from the
submucosa by injecting fluid, most commonly normal saline solution, into the submucosa. A snare is
then placed over the raised area of mucosa, and the mucosa resected with tightening and cautery. Stiff
monofilament snare wires or barbed snares make it easier to grasp the raised mucosa. Using a
double-channel endoscope, the mucosa can be further lifted using a biopsy forceps inside the open snare
for easier grasping and specimen retrieval. This is a variant of the old, risky "lift and cut" method, but
with the added safety of the saline cushion.[5]
The most recent variation of EMR uses the lifting power of endoscopic suction by fitting a cap on the tip
of the endoscope. Special caps have been manufactured to hold an open snare. After injection, the raised
mucosa is suctioned into the cap and the snare closed.[6]
Another variation of this method employs a variceal ligating device to suction the raised mucosa,
followed by the application of a ligating band to create a pseudopolyp for snare resection. The banding
technique, which has been called "band and snare" or "band and cut," is a bit more cumbersome than
standard EMR. However, the equipment is widely available, and the method is arguably the easiest
variation of EMR to perform for small, flat lesions.[7]
In any of the EMR suction-cap methods, even with the new models made of transparent plastic, it is
helpful to mark the area of resection using small cautery burns. This allows easier localization of the
mucosal target to be suctioned and resected, after injection. EMR appears to be generally safe, with low
rates of bleeding and perforation. The risks reported seem to be slightly higher when using suction-cap
techniques. Larger saline injections may help make these latter procedures safer.
The great advantage of EMR, compared with mucosal ablation with techniques such as electrocautery,
laser, or photodynamic therapy, is the retrieval of a specimen for pathology analysis to assess
completeness of the resection. Indeed, EMR was initially designed as a primarily diagnostic technique
called "strip biopsy."[5]
In the West, EMR has been used primarily to assist in piecemeal resection of superficially spreading
carpet-like colon polyps. Other recent applications have been for elevated, focal areas of high-grade
dysplasia and mucosal carcinoma in Barrett's esophagus (generally in patients whose age and comorbid
illness preclude surgery).[8] EMR has also been used as a means of debulking nodular or polypoid lesions
in such patients before photodynamic therapy (PDT) to the entire Barrett's area.[9]
Photodynamic Therapy
PDT is a 2-part therapy. In the first step, a photosensitizing drug is given and accumulates in the tissue to
be treated. Second, the drug is then activated by shining a bright light, usually from a laser, at the target
tissue. The activated drug reacts with oxygen in the environment to induce cell death and tissue necrosis.
An update and review of PDT was presented by Dr. Kenneth Wang. A great deal has been learned in just
a few years regarding the efficacy and safety of PDT in the gastrointestinal tract. Its initial approved use
for palliation of advanced esophageal cancer remains valid.[10] Esophageal cancer frequently presents at
an advanced stage with dysphagia, and in this setting, palliative therapy often is appropriate. However,
competing therapies, including combined radiation therapy and chemotherapy, expandable metal stents,
Nd:YAG laser, and argon plasma coagulator, have decreased the use of PDT for palliation of esophageal
cancer.[11]
PDT has potentially much greater importance in the management of mucosal disease. There has been
considerable research interest in the use of this technique for high-grade dysplasia in Barrett's esophagus,
in the setting of extensive squamous cell dysplasia, and in superficial spreading squamous cell cancer of
the esophagus and superficial gastric cancer.[12-19] The other area of interest has been in the palliation of
cholangiocarcinoma.[20]
The 2 primary photosensitizers currently in use in gastroenterology have been porfimer sodium
(Photofrin) and 5-aminolevulinic acid (5-ALA). Photofrin has been effective in advanced cancer and is
being actively tested for high-grade dysplasia and early cancer in Barrett's esophagus. 5-ALA is easier to
use and has shorter skin photosensitivity and fewer side effects compared with Photofrin, but treatment
effects are very superficial. Laser devices for PDT have improved considerably in recent years with the
development of diode lasers with light wavelengths in the correct range and new light guides for
improved light delivery (eg, centering balloon devices for long segments of Barrett's esophagus).
Argon Plasma Coagulation
No, it's not a laser, as Dr. Jerome Waye of Mount Sinai Medical Center in New York, who presented this
topic, was quick to explain. In this method, originally developed for use in open surgery, argon gas is
passed through a coagulation probe with an electrode at its tip. When the electrode is activated by a foot
switch, a radiofrequency current passes through the argon beam, which results in an ionized plasma that
conducts a spark to the nearest point of tissue contact. The circuit is completed by means of a return
electrode plate on the patient.[21]
Since desiccated tissue is resistant to electrical current, the tissue effect of argon plasma coagulation
tends to be superficial. However, as Dr. Waye emphasized, deeper injury to the muscularis propria and
beyond is possible. In treating areas that have a thinner wall, such as the right colon, Dr. Waye strongly
advised decreasing power and gas flow settings to minimize the risk of deep injury and perforation.
Argon plasma coagulation has been used successfully in the treatment of vascular ectasias, radiation
proctitis, and flat adenomas.[21] There has been considerable interest as well in treating Barrett's
esophagus, but residual Barrett's epithelium beneath new squamous mucosa has been a persistent
problem.[22] Recently, the use of higher power and gas flow settings has led to improved eradication but
also to more complications, including esophageal strictures.[23]
Endoscopic Ultrasonography
Progress in instrumentation and clinical research continue to expand the potential utility of endoscopic
ultrasonography (EUS). This progress was reported by Dr. Charles J. Lightdale from
Columbia-Presbyterian Medical Center in New York. He emphasized the development of high-frequency
miniprobes that can be passed through the channels of standard endoscopes.[24]
A key rule in ultrasonography is that the higher the frequency of the sound waves used, the greater the
clarity of the images, but the shorter the penetration depth. The new miniprobes at 12, 20, and most
recently 30 MHz provide unique images of the wall of the gastrointestinal tract from the esophagus to the
rectum.
The ability to image the wall of the gastrointestinal tract as a series of definable layers corresponding to
histology, rather than as a single entity, results in a powerful clinical tool and is the basis of many of the
indications for EUS. The new miniprobes can be used for evaluation of submucosal lesions, abnormal
folds, esophago-gastric varices, and cancer staging. Evaluating areas of dysplasia and early cancer before
endoscopic therapy with endoscopic mucosal resection or ablation is an important new indication well
suited to miniprobes. New wire-guided probes can be directed into the pancreatic and bile ducts for
evaluation of tumors and stones. A new portable receiver from Olympus (EU-M30S) fits on a cart small
enough for even the most crowded ERCP (endoscopic retrograde pancreatography) room.[25]
Other indications have emerged stemming from the ability of standard EUS to provide detailed images of
areas in immediate proximity to the gastrointestinal tract.[26] In initial clinical trials, EUS appears to be a
sensitive method for the diagnosis of chronic pancreatitis.[27] Radial mechanical instruments continue to
evolve and improve, as do electronic linear instruments, which can be used to guide needles precisely
through the gut wall into surrounding structures.
A relatively new use for EUS-guided fine-needle aspiration is emerging in the staging of non-small-cell
lung cancer. Following diagnosis, the disease is usually staged with computed tomography (CT) scan of
the chest. Large lymph nodes in the posterior mediastinum and subcarinal areas can now be aspirated for
cytologic confirmation of malignancy with EUS guidance. If a lymph node is confirmed to harbor
metastases on the contralateral side of the mediastinum from the tumor, the patient will not be cured by
surgery alone, and a different management plan must be selected. Thus, a positive EUS-guided cytology
can have a major impact on the management of patients with non-small-cell lung cancer. Initial reports
put the accuracy of EUS-guided fine-needle aspiration for this purpose in the range of greater than
90%.[28]
New Trends in Endoscopy
A second symposium addressed the major trends that may have an impact on endoscopic practice in the
future. Dr. Michael Wallace, from the Medical University of South Carolina in Charleston, saw a new
thrust toward making endoscopy more comfortable and acceptable to a wider population with the
development of thinner endoscopes. Instruments as small as 5 mm are in current use, and Dr. Wallace
and his colleagues have been testing endoscopes as small as 3-4 mm in diameter.
The thinner endoscopes have the potential of being used with topical anesthesia only, avoiding the need
for patient sedation. Using these thin instruments, the transnasal route may be preferable in some
patients.[29] Dr. Wallace described an inexpensive, portable, instrument 3.1 mm in diameter, without a
biopsy channel, designed as a screening tool for Barrett's esophagus in patients with symptoms of
esophageal reflux.
Variable Stiffness Colonoscope
Another important development is presently available for colonoscopy: the variable stiffness endoscope.
This instrument allows passage through the sigmoid loops with a flexible setting. Stiffness can then be
increased to allow passage through the transverse colon, and around the hepatic flexure to the cecum.
The variable stiffness colonoscope seems to offer a major advance in allowing more complete
examinations of the colon to be carried out with greater patient comfort.[30,31]
Optical Biopsy
The use of standard biopsy and pathology may also be enhanced or even partly replaced with the
development of "optical biopsy." This approach employs new technology related to advances in optical
science and computer analysis. For example, light-scattering methods may allow an endoscopist to scan
the mucosal surface for dysplasia by analyzing the size of cell nuclei, their arrangement, and their
crowding.[32] A view of surface cells in real time may be possible using endoscopic confocal microscopy.
Fluorescence spectroscopy is also being studied as a potential means of identifying dysplastic areas.[33]
Optical Coherence Tomography
Endoscopic optical coherence tomography (EOCT) is a new method of imaging that is currently being
tested for application in the gastrointestinal tract.[34,35] The method is roughly analogous to EUS, but uses
light instead of sound to produce images with a 10-fold greater resolution. In EOCT the path of reflected
light is measured using a method called interferometry.
Early studies with prototype systems have produced some striking images of the gastrointestinal mucosa
and submucosa, both in vitro and in vivo. Comparison of measurements of architectural layer thickness
in EOCT and histology has shown remarkable equivalence.[34,35]
New Endoscopic Surgery
Dr. Anthony N. Kalloo, from the Johns Hopkins Medical Center in Baltimore, Maryland, described his
studies testing a method he called "flexible endoscopic surgery." This investigation involved a deliberate
perforation of the pig stomach following antibiotic treatment, allowing examination of the peritoneal
cavity and liver biopsy using a standard flexible endoscope. The perforation was subsequently closed
with endoscopic clips. Dr. Kalloo hopes this method may lead to surgical procedures even less minimally
invasive than current laparoscopy, because there will be no skin incisions or puncture sites, thus allowing
even more rapid recovery.
Ensuring the Quality of Endoscopy
Dr. Peter Cotton, the session moderator, from the Medical University of South Carolina, was the final
presenter. He emphasized 3 trends in the current developments in endoscopy. The first aspect, as
discussed by Dr. Wallace, was that endoscopy would become more available, comfortable, and less
expensive. Technology, it was emphasized, would also improve diagnostic accuracy. The second drive in
this field, the development of endoscopic surgery, as demonstrated by Dr. Kalloo, will further blur the
distinction between traditional endoscopy and surgery.
The third trend relates to improved training, practice quality, and accountability. Dr. Cotton saw these
developments as necessary and inevitable. Increasing use of reporting software will lead to
documentation that is needed for quality assurance. Benchmarking of performance will also become the
norm, with computer-generated results.
Concluding Remarks
Web-based learning and the Internet, combined with improved simulation methods, are likely to lead to a
revolution in the way that endoscopists learn and maintain their skills. In the end, these developments
should surely strengthen gastrointestinal endoscopy as a specialty and directly benefit patients
undergoing endoscopic-based procedures.
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16. Barr H. Barrett's esophagus treatment with 5-aminolevulinic acid photodynamic therapy.
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17. Radu A, Wagnières G, van den Bergh H, Monnier P. Photodynamic therapy of early squamous
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18. Sibille A, Lambert R, Souquet JC, et al. Long term survival after photodynamic therapy for
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23. Schulz H, Miehike S, Antos D, et al. Ablation of Barrett's epithelium by endoscopic argon plasma
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24. Chak A, Soweid A, Hoffman B, et al. Clinical implications of endoluminal ultrasonography using
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25. Stevens PD, Lightdale CJ. Evaluation of a new compact ultrasound processor for mini-probe
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27. Sahai AV, Mishra G, Penman ID, et al. EUS to detect evidence of pancreatic disease in patients
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28. Gress FG, Savides TJ, Sandler A, et al. Endoscopic ultrasonography, fine-needle aspiration biopsy
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30. Brooker JC, Saunders BP, Shah SG, et al. A new variable stiffness colonoscope makes
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Barrett's esophagus using light-scattering spectroscopy. Gastroenterology. 2000;119:677-682.
33. Wang T, Wang Y, Crawford J, et al. Fluorescence endoscopic imaging for the detection of colonic
dysplasia. Gastrointest Endosc. 1999;49:477-455.
34. Bouma BE, Tearney GJ, Compton CC, et al. High resolution imaging of the human esophagus and
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35. Sivak MV Jr, Kobayashi K, Izatt JA, et al. High-resolution endoscopic imaging of the
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2000;51:474-479.
New Insights Into Irritable Bowel Syndrome
Kevin W. Olden, MD
Introduction
Irritable bowel syndrome (IBS) is a well-known disorder for both gastroenterologists and primary care
physicians. It has been described traditionally as affecting 15% of the North American population.
However, the diagnosis of IBS has suffered in the past from a lack of precise diagnostic criteria and
difficulties in defining adequate treatment and measuring the impact of that treatment in an effective
manner. A number of research and clinical symposia were presented at the Annual Meeting of the
American College of Gastroenterology that shed new light on the epidemiology, treatment, and
economics of the disease burden of IBS.
The Challenge of Diagnosis
The Rome Criteria
In an attempt to develop standardized diagnostic criteria for clinical practice and research in IBS,
international working teams developed the ROME I diagnostic criteria in 1990. In 1999, those criteria
were revised and simplified, resulting in the ROME II criteria. Investigators have now begun to evaluate
the sensitivity, specificity, and congruence of the ROME II criteria with the ROME I criteria. In one
study, Grant Thompson, MD, and colleagues[1] from the University of Ottawa and McMaster University
in Ontario, Canada, compared the congruence of both the ROME I and II criteria prospectively in a large
population of Canadians. Using standard random telephone polling, the investigators recruited 1149
people, adjusting for demographic variables including age and gender. The prevalence of IBS by ROME
II criteria was 12% compared with 13% using the ROME I criteria. When gender was evaluated, the
prevalence of IBS was found to be 15% in females and close to 9% in males using ROME II, compared
with 18.1% and 18.5% in females and males, respectively, using the ROME I criteria. Investigators
concluded that the new ROME II criteria produced similar results when compared with the older ROME
I criteria. These findings suggest that the ROME II criteria may indeed provide equal efficacy in
identifying patients with IBS while being much simpler to use.
A very different study was presented by M. Zuckerman, MD, from Texas Tech University in El Paso,
and G. Nguyen, MD, from Cho Ray Hospital in Ho Chi Minh City, Vietnam.[2] These investigators
surveyed 516 predominately healthy Vietnamese healthcare workers and relatives of patients treated at
the Cho Ray Hospital. The individuals were surveyed using an instrument that included the ROME I
criteria. A total of 233 individuals (42%) responded. A 6% prevalence of IBS was reported in this
sample. Five percent of males and 7% of females met the ROME I diagnostic criteria for IBS. Of
interest, the gender difference was not significant, putting this study at odds with research done in North
America and Europe where the female-to-male ratio in IBS is skewed toward a higher prevalence in
women. The investigators concluded that IBS in a Vietnamese population may present different
epidemiologic factors, including lower overall presence and less gender variation. This study is important
in that it demonstrates that further epidemiologic studies in populations outside of North America and
Europe are needed to better understand the nature of IBS around the world.
Disease Burden
The issue of the disease burden of IBS has been investigated only recently. Previous studies have
demonstrated the cost of morbidity due to IBS in the United States to be over $8 billion. To further
evaluate the economic burden of IBS, Eisen and colleagues[3] sampled 2354 individuals from large health
maintenance organizations in New Mexico. Of the total contacted, 1032 (44%) agreed to participate in a
telephone survey. Data collected included demographic characteristics, the presence of a diagnosis of
IBS by ROME I criteria, and quality of life measured by the SF-36 questionnaire, a validated general
quality-of-life measure and the IBS-QOL, an instrument that is specific for IBS. Patients were screened
psychologically with a checklist that measured psychiatric comorbidity and levels of psychosocial
distress.
The investigators found that 9% of their sample (94 individuals) met the diagnosis of IBS by the ROME I
criteria. There were no demographic differences, including age, gender, race, marital status, education, or
income between IBS patients and nonpatient responders. The respondents with IBS were found, on
review of their medical records, to have had greater number of outpatient visits in the year preceding the
survey compared with non-IBS respondents. However, IBS responders did not differ from non-IBS
responders in number of hospitalizations. The patients with IBS tended to use more medications and
incurred increased charges for both outpatient visits and prescription drugs. There was also a trend
towards higher total costs for all healthcare services for IBS patients during the year that healthcare
utilization was measured compared with non-IBS responders. The patients who met the ROME I criteria
for IBS had significantly lower scores on the SF-36 compared with non-IBS responders (P < .0001).
The investigators concluded that using a cohort of patients in a managed care organization where
healthcare utilization and costs could be tracked easily demonstrated that IBS sufferers had significantly
more outpatient visits and use of prescription medications than patients without IBS. Further, IBS
patients experienced decreased levels of health-related quality of life as opposed to non-IBS respondents.
The investigators believed that these findings demonstrated a significant disease burden for IBS.
Levy and colleagues[4] presented a similar study that was performed at a large health maintenance
organization (HMO) in the Puget Sound area of Washington State. These investigators performed a
retrospective study of patients who had been diagnosed with IBS. The medical records of 3153 patients
who were diagnosed with IBS were examined and compared with 3153 age- and gender-matched
controls from the same HMO who were not diagnosed with IBS and an additional 3153 individuals who
were also age- and gender-matched who presented for routine checkups and new medical complaints.
Cost of overall care and GI-related costs of care were measured for a 3-year period. The investigators
found that for the index year of diagnosis, the total cost of care for IBS patients was $4044, or $1415
higher than for controls. In addition, the IBS patients continued to have healthcare utilization costs
approximately $1000 more per person than in the 2 subsequent years of tracking after the initial
diagnosis was made.
When GI-related care was specifically measured, the IBS group consumed $582 in the index year; that
was reduced to some degree in the 2 subsequent years after diagnosis. The largest components of
GI-related costs in the first year of the IBS diagnosis were primary care visits ($178), medications
($108), outpatient procedures ($98), radiographic procedures ($77), and specialists' visits ($64). Of
interest, there were no significant differences in the number of emergency department visits, inpatient
care, or laboratory tests between IBS and non-IBS patients. When all medical problems in both the IBS
patients and controls were examined, it was found that less than half of the difference in costs was
explained by the cost of IBS-related care. The investigators concluded that IBS indeed had a greater
cost-of-care burden, particularly in the first year of diagnosis.
Innovations in Treatment
Significant advances in the treatment of IBS have been evolving over the last few years. The increase in
our understanding of the enteric nervous system and the importance of neurotransmitters present in the
gut have been described by various investigators. These findings, in turn, have led to an explosion in
research to develop specific agents that can positively affect neurotransmitter function in the treatment of
IBS patients.
Consequently, the American College of Gastroenterology sponsored a symposium on the treatment of
IBS, which was moderated by Drs. Kevin Olden and Arnold Wald.[5] The symposium addressed the
difficulties of designing valid clinical trials for IBS and identified the psychosocial and gender factors
associated with treatment response as well as the psychiatric and psychological comorbidity that can
influence a patient's behavior and treatment response. The use of antidepressant medications and active
agents now being developed and entering clinical practice were all discussed in detail.
The Difficulties in Designing Clinical Trials
Dr. Nicholas Talley[5] from the University of Sydney, Australia, began the symposium by outlining the
difficulties associated with performing high-quality clinical trials for any therapeutic approaches to IBS
and the methodologic deficiencies of trials published over the last 30 years (including issues of patient
recruitment, lack of standardized diagnostic criteria, lack of controls, inadequate consideration to the
high placebo response rate seen in IBS, and inadequate outcome measures). Dr. Talley concluded that
over these last 3 decades, we have yet to produce a clinical trial that meets the "gold standard." Nor was
there any one trial that we could point to and declare unequivocally the efficacy of any particular
treatment approach. The absolute importance of maximizing methodologic quality in testing any
proposed treatment for IBS was emphasized, lest erroneous or inaccurate conclusions be drawn.
Important to further emphasize is that this literature, although advancing quite rapidly, is still immature
and thus there are additional lessons to be learned in planning the "ideal" IBS clinical trial.
The Role of Psychosocial and Hereditary Factors
Dr. Rona Levy[5] from the University of Washington focused on recent research on family dynamics and
heredity as they influence IBS expression in patients. In her research, Dr. Levy found that patients with
IBS were slightly more likely to have children who would also develop IBS. However, Dr. Levy was
quick to emphasize that the reasons for this association remain unclear. Whether this finding represents a
genetic phenomenon, as proposed by some investigators, or socialization, family dynamics, or learned
healthcare behavior needs to be further determined. Identifying these issues has important treatment
implications because there may be a strong level of concern and anxiety within a family about the
significance of IBS and its effect on that family that in turn, can influence patient behavior.
Data were also presented demonstrating that women have a tendency to respond differently from men to
visceral pain, which in turn may influence response to drug treatment. The importance of designing trials
adequately balanced between men and women and paying attention to gender-based response differences
is clearly important for generating high-quality data on drug and other interventions for IBS.
Psychologic Comorbidity
Dr. Arnold Wald from the University of Pittsburgh Medical Center reviewed the prevalence of
psychiatric comorbidity in patients with IBS.[5] Dr. Wald discussed well-established data showing the
high prevalence of anxiety disorders, particularly panic disorder, mood disorders, and somatization
disorder in patients with IBS. It should be emphasized that IBS is not a psychological disorder and does
not represent "a form fruste" of a psychiatric disorder. Rather, it is important to understand psychiatric
disorders as comorbid conditions that can influence presentation, healthcare seeking, drug response, and
prognosis. Using case studies, Dr. Wald presented psychiatric-disorder patients from his practice who, at
first view, would seem to have IBS. Likewise, he presented patients with IBS who, although distressed,
did not have a diagnosable psychiatric disorder on further investigation but who could have easily been
misperceived as having one.
Dr. Wald presented illustrative cases to demonstrate the importance of taking an adequate history and the
utility of office-based psychological screening instruments for identification of psychological issues. Dr.
Wald stressed the ease of using these screening instruments in this setting, their applicability to
office-based practice, and how to present them to the patient in a positive and helpful manner.
The Role of Antidepressants*
The use of antidepressants in IBS was discussed by Kevin Olden, MD, of the Mayo Clinic in Scottsdale,
Arizona.[5] Dr. Olden reviewed the history of antidepressants in gastroenterology. Specifically, the
anticholinergic properties of the older tricyclic antidepressants and their presumed effect on GI motility
and the usefulness of tricyclic antidepressants in the treatment of neuropathic nongastrointestinal pain
syndrome, such as peripheral neuropathy, were addressed. Dr. Olden also described the effect of
neurotransmitter systems found in the gut. He reviewed clinical trials, particularly those by Greenbaum,
Cannon, and Clouse, that investigated the use of desipramine,* imipramine,* and trazodone,*
respectively, for treating functional gastrointestinal disorders.
Dr. Olden emphasized the commonality of the findings of these separate trials using 3 different
antidepressants. In all of them, the subjects had no significant demonstrable changes in gastrointestinal
motility nor any significant changes in their psychiatric status as a result of the antidepressant
intervention. However, the patients did have significant improvement in their GI symptom ratings as well
as -- most important -- significant improvement in their overall sense of well being. Dr. Olden
emphasized that these findings suggest a site of action of antidepressants both in the gut as well as in the
central nervous system where the sensations produced in the gut by IBS are processed and modulated to
produce the patient's "report" of his or her symptoms. Patients can begin on low doses of these
antidepressants and are less likely to experience troublesome side effects. Dr. Olden stressed the
importance of understanding that these drugs, when used in the setting of IBS, are an "off-label"
indication, and, therefore, physicians should proceed with caution and ensure their patients'
understanding of the reasons for their use.
Finally, Dr. Olden reviewed the opportunities that are emerging for the use of antidepressants in
gastroenterologic practice. The development of an ever increasing number of new antidepressive agents,
including the selective serotonin reuptake inhibitors (SSRIs) and agents that tend to have lower side
effect profiles, all deserve further study in GI practice to help define their role in treating IBS and other
functional gastrointestinal disorders (such as functional dyspepsia, esophageal dysmotility, and
functional abdominal pain).
The Role of Serotonin
The session was concluded by Dr. Lin Chang from the UCLA School of Medicine, who addressed the
use of newer serotonergically active agents for IBS. Dr. Chang reviewed the significance of serotonin as
a target neurotransmitter in the therapeutic intervention of the functional gastrointestinal disorders. She
emphasized that 95% of serotonin contained in the body is located in the gastrointestinal tract, with the
extraneous 5% being primarily located within the brain.
Dr. Chang presented the latest data on alosetron (Lotronex), a 5HT3 antagonist and a significant inhibitor
of gastrointestinal motility. This inhibitive property makes alosetron an ideal agent for the treatment of
diarrhea-predominant IBS. Dr. Chang also discussed the clinical data supporting the efficacy of alosetron
in reducing stool frequency in patients with diarrhea-predominant IBS and its ability to decrease
abdominal pain and rectal urgency. Other properties of the drug include a lack of adverse interactions,
the need for dose adjustment with age, and the absence of metabolic changes in patients with renal or
liver dysfunction. Because of its significant antiprokinetic effect, alosetron can commonly produce
constipation, which occasionally can be severe. It is important for the physician to be proactive in
treating constipation early if seen in these patients.
Dr. Chang also presented data on agents still in development, including tegaserod and prucalopride, both
of which act on 5HT4 receptor sites. These drugs are being developed specifically for the treatment of
constipation-predominant IBS because of their prokinetic effect. Preliminary data published to date
studying the effect of tegaserod on gastrointestinal transit and its ability to decrease bloating and
abdominal pain in patients with constipation-predominant IBS appear promising.
Additional Studies and Strategies for IBS
Drotaverine
In addition to this symposium on the treatment of IBS, a number of clinically relevant research abstracts
were presented. Misra and colleagues[6] from the University of New Delhi Medical School in India
presented the results of a randomized double-blind, placebo-controlled trial of drotaverine for the
treatment of IBS. Drotaverine is a selective inhibitor of phosphodiesterase isoenzyme IV, which has been
found useful in smooth muscle motility disorders. Seventy consecutive patients between the ages of 18
and 60 diagnosed with IBS using their own criteria were studied in this prospective trial. Patients were
treated with drotaverine 80 mg 3 times a day and compared with placebo during a 4-week trial and an
additional 4-week follow-up period. These investigators found that drotaverine significantly reduced pain
compared with placebo (P < .001). Pain severity scores also increased significantly in the drotaverine
group compared with placebo (P < .001). Patients treated with drotaverine also experienced significant
improvement in global relief of abdominal pain, again compared with placebo (P < .001), and significant
improvement in stool frequency (P < .001). No adverse effects were observed in any of the patients
either in the placebo or treatment groups. The study authors concluded that drotaverine produced
significant global improvement in abdominal pain in patients with IBS.
Alosetron
Recently, the 5-HT3 antagonist alosetron was approved by the FDA for the treatment of
diarrhea-predominant IBS in women. And, in the wake of this, a number of new studies were presented.
Jhingran and colleagues[7] studied patient satisfaction in individuals with nonconstipated IBS treated with
alosetron. A total of 801 women were studied using a 12-week randomized, double-blind,
placebo-controlled multicenter trial of alosetron 1 mg twice daily. These investigators found that overall
satisfaction in those patients treated with alosetron was significantly higher than in the placebo group (P
< .001). On entry into the trial, less than 10% of all subjects reported that they were either satisfied or
extremely satisfied with their previous IBS treatment regimens. In contrast, at the conclusion of the
alosetron trial, 12 (69%) of the subjects treated with alosetron reported that they were either satisfied or
extremely satisfied with treatment compared with only 42% of the controls (P < .001). They also found a
high correlation between overall patient satisfaction as well as satisfactory control of rectal urgency and
global improvement of all IBS symptoms. Constipation was the only adverse event reported significantly
more frequently in the treatment group (39% vs 14% of controls). The study authors concluded that
above and beyond standard outcome measures such as decreased pain and change in bowel movements,
patients treated with alosetron also experienced high levels of satisfaction with their care.
In a related study, Markowits and colleagues[8] studied the efficacy of alosetron in patients with rectal
urgency. Over 800 patients were studied in a 12-week randomized, double-blind, placebo-controlled
multicenter trial of the efficacy and tolerability of alosetron 1 mg twice a day. (During the screening
period, subjects had reported a lack of satisfaction with control of their symptoms of bowel and rectal
urgency at least 50% of the time.) This factor was followed throughout the course of the clinical trial
over 12 weeks. The study authors found that patients treated with alosetron were significantly more
likely to report improvement in rectal or bowel urgency (P < .001). There was a high correlation seen
between improvement in global well-being and satisfactory control of rectal urgency at week 12 (r =
0.54). The investigators concluded that alosetron selectively improved control of rectal urgency in the
context of global improvement of IBS symptoms compared with placebo.
[Ed. note: Recently the FDA announced the development of a medication guide (FDA-approved patient
labeling) to help ensure that women using the prescription drug alosetron hydrochloride for treatment of
the diarrhea-predominant form of IBS will understand the rare but serious risks of this drug and how they
can recognize those risks and take early action to prevent serious harm. These risks include
complications from constipation and the risk of ischemic colitis, which is caused by reduced blood flow
to the intestines.]
Acupuncture?
Lu and colleagues[9] discussed the use of acupuncture, investigated in a randomized, controlled trial of 27
patients with IBS diagnosed by their own criteria and assigned to receive acupuncture treatment or
relaxation sessions. Using a crossover design method, the subjects received both modalities. In addition
to demographic information and specific IBS symptoms reported, patients also rated their overall quality
of life on entry to and exit from the study. The study authors treated the patients with acupuncture or
relaxation sessions 3 times a week for a period of 2 weeks. A follow-up observation run was then
performed for 4 weeks.
These investigators found that patients' quality-of-life and gastrointestinal symptom scores were
improved equally in the 23 who completed both the acupuncture trial and the relaxation sessions. A
statistically significant reduction in abdominal pain was observed in both groups at the end of the trial.
However, when the patients were followed for the 4-week period posttrial, only in the acupuncture group
did pain reduction persist (P < .05). Furthermore, a significant reduction in stress perception was also
observed in the acupuncture group, but not in the relaxation group (P < .05). It was concluded that
acupuncture appears to be an effective modality in the treatment of IBS, particularly for pain and
disease-related stress, and exceeds standard relaxation treatment. This intriguing finding is of particular
interest because of the increasing attention paid to so-called alternative treatments for IBS by patients
and the medical community itself. Additional studies will be needed to confirm these results. The work
of Lu and colleagues, however, is an important step in this direction. Clearly, acupuncture as well as
other alternative modalities deserve additional study in this disease setting.
Conclusion
Irritable bowel syndrome continues to pose a significant challenge to the physician in terms of both
diagnosis and management. The material presented during these meeting proceedings serves to
underscore not only the progress that has been made in recognizing this disease entity (eg, establishment
of the Rome Criteria), but also the promise of new therapeutic interventions (eg, tegaserod) that are
waiting in the wings.
* The United States Food and Drug Administration has not approved this medication for this use.
References
1. Thompson GW, Irvine JE, Pare P, et al. Comparing Rome I and Rome II criteria for irritable bowel
syndrome in a prospective survey of the Canadian population. Program and abstracts of the 65th
Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000,
New York, NY. Poster 312, p. 461.
2. Zuckerman MJ, Nguyen G, Ho H, et al. Prevalence of irritable bowel syndrome according to the
Rome criteria in a Vietnamese population. Program and abstracts of the 65th Annual Scientific
Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY.
Poster 314, p. 462.
3. Eisen GM, Weinfurt KP, Hurley J, et al. The burden of irritable bowel syndrome in a community
sample. Program and abstracts of the 65th Annual Scientific Meeting of the American College of
Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 20, p. 175.
4. Levy R, Stang P, Von Korff M, et al. Longitudinal study of the comparative costs of IBS in an
HMO. Program and abstracts of the 65th Annual Scientific Meeting of the American College of
Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 28, p. 186.
5. Olden KO, Wald A, et al. Treatment of irritable bowel syndrome. Program and abstracts of the
65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18,
6.
7.
8.
9.
2000, New York, NY. p. 51.
Misra S, Pandey R. Efficacy of drotaverine in irritable bowel syndrome: a double blind,
randomized, placebo-controlled trial. Program and abstracts of the 65th Annual Scientific Meeting
of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Oral
presentation 29, p. 187.
Jhingran P, Bagby B, Decker C, et. al. Patient satisfaction in Lotronex[R] (alosetron HCL) treated
nonconstipation irritable bowel syndrome in females. Program and abstracts of the 65th Annual
Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York,
NY. Poster 387, p. 518.
Markowits M, Bagby B, Gordon S, et al. Satisfactory control of bowel urgency and global
improvement in irritable bowel syndrome with LotronexR (alosetron therapy). Program and
abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology;
October 16-18, 2000, New York, NY. Poster 489, p. 596.
Lu B, Hu Y, Tenner S. A randomized controlled trial of acupuncture for irritable bowel syndrome.
Program and abstracts of the 65th Annual Scientific Meeting of the American College of
Gastroenterology; October 16-18, 2000, New York, NY. Poster 268, p. 428.
Barrett's Esophagus: The Challenge Continues
M. Brian Fennerty, MD
Barrett's Esophagus: Why All the Interest?
For over a decade, adenocarcinoma of the esophagus has been recognized as the most rapidly rising
incident tumor of any cancer in the United States and Western Europe. In the year 2000, esophageal
cancer will result in nearly 12,000 deaths in the United States alone, with the majority being
adenocarcinoma that arises from its precursor lesion, Barrett's esophagus (BE). Despite extensive
research interest in this disease, many questions remain regarding the pathogenesis, incidence and
prevalence, natural history, effectiveness of currently recommended screening and surveillance
strategies, and therapeutic approach to BE. This article discusses the latest data on BE as reported in
abstracts and educational symposia presented at this year's Annual Meeting of the American College of
Gastroenterology.
Can We Identify the Patient at Risk of Having BE?
Chronic symptoms of gastroesophageal reflux disease (GERD) occur in 20% of adult Americans and
10% to 15% of adults with chronic GERD will have BE. The characteristics of the chronic refluxer that
determine who will and will not develop BE are as yet undetermined. Because of this inability to predict
risk, current recommendations are to screen for BE in all patients with GERD symptoms of greater than 5
years' duration. This recommended practice management strategy necessitates that 85% or more of reflux
patients without BE undergo a costly and invasive endoscopic procedure. Ideally, if clinical factors could
be identified that differentiated risk for BE, then a more effective clinical and economic screening
strategy could be devised.
Avidan and colleagues[1] from the VA Medical Centers in Albuquerque, New Mexico, and Hines,
Illinois, performed a case-control study aimed at identifying potential risk factors for BE in reflux
patients. Additionally, they sought to determine risk factors for length of Barrett's because many
investigators believe columnar length correlates with cancer risk. In the study, 256 GERD patients with
BE were compared with 229 GERD patients with nonerosive reflux disease. All cases and controls had
undergone endoscopy, manometry, and ambulatory intraesophageal pH monitoring. Patients with BE
were found to have more frequent reflux, were more likely to have a hiatal hernia (76% vs 36%), be
white (96% vs 85%), and smoke (87% vs 76%). Frequency of reflux, hiatal hernia, smoking, alcohol use,
and the magnitude of intraesophageal acid exposure were also identified as being associated with a
greater length of BE. Based upon these findings, the investigators concluded that BE was associated with
clinical factors indicating more severe reflux disease.
These clinical, endoscopic, and pH data correlate with a recent case-control study of the association
between esophageal adenocarcinoma and more frequent, severe, and longer-duration reflux symptoms.
Thus, more severe GERD, either based on symptoms or objective testing by endoscopy or pH
monitoring, is indicative of an increased risk of having BE. Whether a discriminating predictive tool can
be developed from data such as these in order to assist the clinician in determining who should be
screened is unknown, but there does appear to be some potential for such an instrument.
Once We Diagnose BE, What Do We Do?
Once a patient is determined to have BE, current recommendations and the standard of care in most
communities dictate performing periodic endoscopic surveillance exams in an effort to identify incident
neoplasia at an early, treatable, and curable stage. The benefit of such surveillance strategies remains
unproven and the ideal timing, technique, and marker of cancer risk is unknown. At this time, the marker
indicating the greatest cancer risk has been the identification of high-grade dysplasia (HGD). The
following 2 studies address the issues regarding knowledge and adherence of current practice guidelines
for BE and investigate the use of a novel marker of cancer risk.
Adherence to Practice Guidelines
In 1998, the American College of Gastroenterology published a practice guideline on BE. These
guidelines were also endorsed by the American Gastroenterological Society and the American Society
for Gastrointestinal Endoscopy. This guideline was based on the best available evidence at that time and,
where evidence was lacking, on consensus expert opinion. Cruz-Correa and associates[2] from The Johns
Hopkins University investigated gastroenterologists' awareness and adherence to these guidelines and
also identified factors associated with adherence to these recommendations.
In this prospective study, a survey questionnaire consisting of 3 case scenarios was administered before
publication of the guideline and again 18 months later. Sixty-five percent of those sent the survey
responded, and only 65% of those gastroenterologists were aware that the guidelines existed. Somewhat
surprising, awareness was not associated with adherence to the guidelines. Overall adherence increased
from 27% to 38% (P = .04) and adherence for nondysplastic BE increased from 72% to 81% (P = .03),
but there was no change in adherence for dysplastic BE, either before or after publication of the
guidelines. Adherence was less likely in a fee-for-service environment and among older
gastroenterologists. Based upon these data, it was concluded that awareness of the guidelines was
insufficient and that adherence was based on a physician's agreement with the recommendations. It was
also believed that the major barrier to adherence included insufficient data supporting the
recommendations. I would conclude that additional work needs to be done to justify and confirm the
effect of these guidelines. However, these data also suggest that financial incentives in a fee-for-service
environment and the lack of continuing education in older physicians are other important barriers that
must be quickly overcome.
Markers of Cancer Risk
In patients with BE undergoing endoscopic surveillance exams, HGD found on mucosal biopsy is the
currently accepted gold standard for cancer risk. However, HGD may not be the optimal marker because
it is subject to inter- and intraobserver error and may be missed with routine endoscopic biopsy.
Additionally, unrecognized cancer is found to coexist in only 25% to 40% of patients with HGD and the
incidence of cancer is less than 50% over 5 years. Many other markers of cancer risk, including flow
cytometric abnormalities and p53 mutation, among others, have also been evaluated as either substitutes
for HGD or as adjunctive tests to HGD.
Barrett's esophagus is defined as the presence of intestinal metaplasia within the tubular esophagus.
Intestinal metaplasia is characterized by the presence of goblet cells and occasionally noted Paneth cells.
Human defensin 5 (HD5) is expressed in Paneth cells. Shen and colleagues[3] from the Cleveland Clinic
sought to determine whether HD5 could be used to identify BE and/or correlate with the presence or
absence of neoplasia within BE. Using a novel monoclonal antibody to HD5, histochemical techniques
were used to demonstrate that normal squamous mucosa did not have HD5 expression, whereas HD5 was
increasingly expressed as Barrett's mucosa as it progressed from dysplasia to cancer. The location of
HD5 expression also correlated with whether dysplasia or cancer was present with HGD and cancer
expressing HD5 on the surface as well as the glands. It was concluded that HD5 might be another useful
marker of neoplasia in the setting of BE.
I would emphasize that further efforts such as this are needed to determine the optimal marker of cancer
risk. However, at this time the presence of HGD remains the gold standard for cancer risk in this
population of patients.
Is There Evidence That We Can Eliminate Cancer Risk, or BE Itself,
With Endoscopic, Surgical, or Pharmacologic Therapies?
Symptoms of GERD in patients with BE can be effectively eliminated with surgical or pharmacologic
antireflux therapies. However, regression of BE does not occur with these interventions alone. Because
of the inability to effect regression of Barrett's mucosa with antireflux therapies, secondary prevention of
cancer through chemoprevention and/or endoscopic elimination of Barrett's from the esophagus is being
actively investigated. For example, abnormal proliferation and differentiation in BE is normalized by
elimination of pathologic intraesophageal acid exposure. Additionally, it has been demonstrated that
endoscopic injury to the esophagus applied thermally or chemically in conjunction with antireflux
therapy can cause endoscopic reversal of BE. However, neither of these approaches has been shown to
eliminate cancer risk or the need for continued surveillance.
Is Control of Reflux Sufficient?
Carlson and colleagues[4] from Cleveland, Ohio; Tucson, Arizona; and Houston, Texas, sought to
determine whether potent antisecretory therapy with a proton pump inhibitor (PPI) in patients with BE
altered malignant progression in those already exhibiting genomic instability, as measured by p53
mutation. Six patients with p53 mutation and 7 patients without this mutation were followed for a mean
of 5 years. Two of 3 patients with the mutation developed incident dysplasia over that time vs none of
those without the mutation. In patients with p53 mutation, DNA ploidy abnormality persisted or
developed in 83% vs 43% of those without p53 mutation. These findings showed that aggressive
antisecretory therapy failed to halt progression of neoplasia in patients who had already developed a
defect in a DNA repair gene.
I interpret these data to indicate that control of reflux will be unlikely to influence carcinogenesis if
applied late in the process, but that this does not rule out the possibility of using acid suppression as a
chemopreventive strategy earlier in the process. Perhaps reversal is not a necessary endpoint of therapy,
and what we may need is simply early enough intervention with antisecretory drugs. This concept will
require confirmation in a carefully designed clinical trial, determining outcome of this approach.
Reversal of BE
There has also been intense interest in using endoscopic techniques combined with antisecretory therapy
to reverse BE. The optimal technique(s) and outcomes of these therapies is as yet unknown. All of the
described endoscopic approaches have been performed in conjunction with either pharmacologic or
surgical antisecretory therapy. Whether normalization of intraesophageal acid exposure is required for
these techniques to be successful is not known.
Sampliner and coworkers[5] from the University of Arizona used pH monitoring data to correlate the
outcome of endoscopic reversal using multipolar electrocoagulation (MPEC) therapy to esophageal acid
exposure. Patients were administered 40 mg omeprazole twice daily and pH monitoring was performed
prior to the endoscopic therapy. Three of 20 patients continued to have abnormal intraesophageal acid
exposure despite this high-dose PPI therapy, and all had successful endoscopic and histologic reversal.
Three of the remaining 17 patients with normal esophageal acid exposure had continued evidence of BE
after therapy.
These data indicate that normalization of intraesophageal acid exposure is not a prerequisite to
endoscopic elimination of BE. However, the lowest effective dose allowing reversal is not known and
will require further study.
What Happens to Patients With HGD When Treated by One of These
Endoscopic Reversal Techniques?
Photodynamic therapy (PDT), argon plasma coagulation (APC), laser, MPEC, and other endoscopic
techniques have been used to manage BE patients with and without dysplasia. In patients with HGD who
are either unable to have surgery or refuse to have surgery, PDT is the only technique for which there are
sufficient data to suggest a possible therapeutic effect. Sharma and colleagues[6] from the University of
Kansas and the University of Arizona reported on 8 patients with HGD treated with a combination of
Nd:YAG laser and MPEC thermal therapy. At most recent follow-up, 3 had no residual BE, 1 had
nondysplastic Barrett's, 3 had low-grade dysplasia only, and 1 had persistent HGD. This technique,
which is more widely available than PDT, may become a reasonable alternative in this patient
population.
In Patients With Heartburn or BE, What Is the "Real" Risk of
Developing Esophageal Adenocarcinoma?
We have been hampered in our understanding of the natural history of BE because of insufficient data on
which to analyze risk. The limited data that have been available are either contradictory or subject to
various interpretations. In an effort to assess what is known about cancer risk in patients with either
heartburn or BE, Walter Peterson, MD, Professor of Medicine at the University of Texas, Southwestern,
and Philip Schoenfeld, MD, Associate Professor of Medicine at the University of Michigan, co-chaired a
symposium addressing these issues.[7]
The symposium was based on 2 focused questions in evidence-based medicine (EBM):
1. Among patients with heartburn occurring daily for 6 or more years, what is the likelihood of
developing esophageal adenocarcinoma?
2. Among patients with BE, what is the likelihood of developing esophageal adenocarcinoma 5 and
10 years after the diagnosis of BE?
Dr. Schoenfeld discussed the methodology of EBM in a critical appraisal of a study investigating harm.
Methodology, validity, the results (odds ratios and relative risk), and how to determine whether the
results can be applied to a specific patient were discussed as an overview.
Hashem El-Serag, MD, Assistant Professor of Medicine at Baylor University, discussed an
epidemiologic investigation conducted by Lagergren and colleagues[8] of the possible association
between gastroesophageal reflux (frequency, duration, and severity) and esophageal adenocarcinomas.
Based on data presented, the overall conclusion was that there was good evidence and probably a causal
relationship between GERD and this cancer. Thus, the more frequent, the more severe, and the longer the
period of reflux symptoms, the greater the risk for esophageal adenocarcinoma.
Prateek Sharma, MD, Assistant Professor of Medicine at the University of Kansas, analyzed the literature
regarding incidence of cancer in patients with BE. Using 2 inception cohort studies from the University
of Arizona and the Cleveland Clinic,[9,10] he concluded that the incidence of adenocarcinoma in these
patients was between 0.4% and 0.5% per year.
Richard Sampliner, MD, Professor of Medicine at the University of Arizona, continued the trend by
addressing our current EBM knowledge of BE and what is lacking.[7] The consensus was that,
unfortunately, very little is known outside of those data discussed above. While it is clear that the risk of
adenocarcinoma is increased dramatically in patients with BE or heartburn, the overall incidence of this
cancer remains low in this population. Whether the rates are sufficient to justify currently recommended
screening and surveillance strategies cannot be determined from our present knowledge base.
Well-designed clinical trials will be needed to answer this and other clinically important questions
regarding this disease entity.
Summary
The material discussed during these proceedings underscores the significant deficits in the information
upon which to base clinical decision making in patients with BE. It further emphasizes the importance of
additional research regarding this clinically important disease. Hopefully, new data arising during the
next several years will enable us to stratify risk and confirm the effectiveness of therapy in these patients.
References
1. Avidan B, Sonnenberg A, Schnell TG, et al. Risk factors for Barrett's esophagus [abstract]. Am J
Gastroenterol. 2000;95:2412.
2. Cruz-Correa M, Cary G, Canto M, et al. The impact of practice guidelines on management of
Barrett's esophagus: A prospective cohort [abstract]. Am J Gastroenterol. 2000;95:2627.
3. Shen B, Dumot J, Skacel M, et al. Expression of human defensin-5 in Barrett's esophagus
4. Carlson N, Lechago J, Richter J, et al. Proton pump inhibitor (PPI) treatment may not alter
malignant progression in cases of Barrett's metaplasia (BM) showing p53 protein accumulation
5. Sampliner R, Camargo L, Fass R. Impact of esophageal acid exposure on the endoscopic reversal
of Barrett's esophagus (BE) [abstract]. Am J Gastroenterol. 2000;95:2433.
6. Sharma P, Jaffe P, Bhattacharyya A, et al. Fate of high grade dysplasia at 1 year after endoscopic
ablation with Nd:YAG laser and electrocautery [abstract]. Am J Gastroenterol. 2000;95:2433.
7. Peterson W, Schoenfeld P, El-Serag H, et al. Symposium - An evidence-based approach to
Barrett's esophagus and esophageal adenocarcinoma. Program and abstracts of the 65th Annual
Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York,
NY.
8. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor
for esophageal adenocarcinoma. N Engl J Med. 1999;340:825-831.
9. Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barrett's esophagus:
a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol. 1997;92:212-215.
10. O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's
esophagus: report on the Cleveland Clinic Barrett's esophagus registry. Am J Gastroenterol.
1999;94:2037-2042.
Chronic Hepatitis C
Rowen K. Zetterman, MD, FACP, FACG
Introduction
Chronic hepatitis C represents a significant public health challenge in the United States. Approximately 4
million Americans are infected with the hepatitis C virus (HCV), and an additional 35,000 new cases
occur each year. Only 15% of patients who become infected appear to spontaneously clear the virus,
meaning that approximately 85% of infected individuals will develop chronic viral hepatitis C.
Reflecting the urgency of this growing problem in healthcare, a number of research and clinical symposia
held at the Annual Meeting of the American College of Gastroenterology focused on the epidemiology,
clinical features, and medical management of chronic hepatitis C.
Epidemiology
Dr. Mitchell Shiffman of the Medical College of Virginia, introduced a clinical symposium by
establishing that approximately 1.8% of the American population is infected with HCV, with African
Americans about 2 times more likely to be infected than whites. The peak prevalence of chronic hepatitis
C is in the fourth and fifth decades of life, with men more likely to be infected than women.
Screening
The most commonly used screening test is the ELISA II study for detecting antibody to HCV
(anti-HCV). While the recombinant immunoblot assay (RIBA test) has been used in the past to confirm
the likelihood of HCV disease, measurement of circulating HCV RNA is often most helpful in
confirming HCV infection, especially in those with normal aminotransferase levels, those who lack risk
factors for infection, and in those with other liver diseases (such as autoimmune hepatitis), where both
the antinuclear antibody (ANA) and anti-HCV may be present. Measurement of HCV RNA is also
indicated for monitoring treatment response during therapy. Dr. Shiffman noted that the titer of HCV
RNA remains fairly constant during HCV infection in most patients. HCV RNA titer does not appear to
be related to histologic severity of the associated liver disease. There are several genotypes of HCV.
Approximately 70% of HCV-infected individuals in the United States are infected with genotype 1 (ie,
1a or 1b). This genotype is typically more resistant to conventional interferon-ribavirin therapy than are
HCV genotypes 2 or 3.
Disease Progression
Among those individuals infected with HCV, at least 20% will develop progressive liver disease and,
ultimately, cirrhosis. Other concomitant risk factors such as ethanol consumption will increase the
likelihood of developing cirrhosis, and therefore, all patients who are anti-HCV positive should be
strongly encouraged to avoid alcohol. Of those individuals who go on to develop cirrhosis,
approximately 50% will show signs of decompensation (eg, ascites, coagulopathy, or encephalopathy)
within 5-10 years.
While many individuals with HCV infection are asymptomatic, depression appears to be common. When
quality-of-life measurements are used, the patient with known HCV infection shows an overall reduction
in score.
While hepatic histology remains the gold standard for determination of cirrhosis in HCV-infected
individuals, Mark Cumings and colleagues[1] of Walter Reed Army Medical Center in Washington, DC,
presented a poster that showed that patients with a concomitantly elevated serum alkaline phosphatase
were 5.7 times more likely to have cirrhosis than those whose alkaline phosphatase levels were not
increased. The study authors evaluated more than 500 patients who were HCV-RNA-positive by
studying both serum alkaline phosphatase and aminotransferase levels. The ratio of aspartate
aminotransferase (AST) to alanine aminotransferase (ALT) was also determined. As noted, those patients
with an elevated alkaline phosphatase were more likely to have coexisting cirrhosis. An AST/ALT ratio
greater than 1 was observed in 17% of patients and this was also indicative of more significant
underlying histologic disease.
Screening for Hepatocellular Carcinoma
Patients who are infected with HCV have an increased risk of developing hepatocellular carcinoma
(HCC) when compared with uninfected individuals. In a breakfast session held at the Annual Meeting of
the American College of Gastroenterology, Dr. Robert S. Brown from the Columbia University College
of Physicians and Surgeons, in New York,[2] reported that the annual incidence of HCC in patients with
chronic hepatitis C and cirrhosis could be as high as 5%. In a related poster presentation, Dr. Birdi and
colleagues[3] of the Louisiana State University Health Sciences Center, in New Orleans, also suggested
that the combination of HCV and hepatitis B virus (HBV) infection may be more likely to result in
development of HCC as well, and that this factor could explain the increased risk for this malignancy in
African Americans. In a population of 39 patients with HCC in whom both HCV and HBV testing was
done, 36% of African Americans were positive for both viruses, while only 7% of whites were similarly
coinfected. Although this is a small study, it does raise an interesting question that can be further
evaluated with larger patient cohorts that have both HCV and HBV coinfection.
How should HCV-infected patients who also have cirrhosis be screened? To help answer this question,
Dr. O.S. Lin and colleagues[4] of Stanford University in Palo Alto, California, presented a Markov
decision analysis model of patients with HCV-related cirrhosis to determine the cost-effectiveness of
screening with transabdominal ultrasound and serum alpha-fetoprotein (AFP). The study authors
compared abdominal ultrasound and AFP testing at 6 monthly intervals to ultrasound every 12 months vs
no screening, in a model population of 40 year-old, HCV-infected individuals with Child's class A
cirrhosis. Screening was found to be most cost-effective when compared with no screening, when hepatic
ultrasounds were done at 12 monthly intervals. Screening every 6 months, however, had the most
expected gain in quality life-years for those who developed HCC. The cost-effectiveness of annual
hepatic ultrasounds and AFP screening was approximately $31,000 per quality-adjusted life-year gained.
I believe these data suggest that the practice of annual ultrasound evaluation of the liver with annual or
semi-annual AFP measurement is a reasonable approach to screening those persons at risk for HCC who
are infected with HCV and have cirrhosis.
Treatment of HCV Infection
Combination Interferon/Ribavirin Therapy
In a clinical symposium addressing management issues in HCV, Dr. Michael Fried[5] indicated that the
combination of interferon-alpha with ribavirin represents the current recommended therapeutic strategy
for patients with HCV infection. A sustained response of approximately 38% overall for loss of HCV
RNA was reported previously for the US trial of interferon/ribavirin combination therapy. When the
American and European trials are combined, those patients with HCV genotypes 2 and 3 do better with
combination interferon and ribavirin, with approximately two thirds clearing virus vs only about one
quarter of those with genotype HCV1. Furthermore, patients with genotypes 2 and 3 only require 6
months of therapy to produce a sustained response, whereas those with genotype 1 should receive 1 year
of therapy. For patients with HCV genotype 1 who still have abnormal liver tests and HCV viremia after
6 months of therapy, therapy can be stopped because it is unlikely that continued treatment will result in
clearance of the virus.
Should Patients With Normal Liver Function Tests Be Treated With Combination
Therapy?
Whether patients with HCV infection who have normal liver tests should be treated with combination
interferon/ribavirin remains controversial. Data reported from previous trials of interferon monotherapy
in patients with chronic HCV infection and normal liver tests have raised some concern about worsening
liver disease in nonresponders. Dr. Hassanein and colleagues[6] from the University of California in San
Diego, evaluated combination therapy with interferon and ribavirin in 20 patients with normal
aminotransferases, some of whom had induction therapy with higher-dose interferon. In this study,
patients with normal liver tests had similar response rates to those reported in previously published
studies of those with abnormal liver tests. In addition, there was a further reduction in the serum ALT
values with treatment in patients with normal aminotransferase levels. As reported in other studies, these
investigators also noted that those with normal liver tests tended to have milder histologic disease at
biopsy before treatment.
In a related poster session, Dr. Pena and colleagues[7] from Albert Einstein Medical Center in
Philadelphia, Pennsylvania, presented data on 28 patients with normal liver tests and HCV infection.
Patients with normal aminotransferase levels appeared to have an increased treatment response at the end
of treatment, but did not show any difference in sustained response over those whose pretreatment
aminotransferases were elevated. These studies further suggest that combination therapy can be given to
those with HCV infection and normal liver tests. However, some investigators still believe that large
clinical trials should be completed before making combination therapy with interferon/ribavirin for those
with normal liver tests and HCV infection the standard of practice.
Can the HCV Patient With Compensated Cirrhosis Be Treated?
Data from previous studies of interferon monotherapy have suggested that although patients with
compensated cirrhosis from HCV can be treated, they will have a reduced response to treatment. Dr.
Pereyra and colleagues[8] from Albert Einstein Medical Center in Philadelphia enrolled 23 patients with
cirrhosis in a combination interferon/ribavirin treatment trial and compared their outcome with 67
patients without cirrhosis. All patients had previously failed sustained response to interferon
monotherapy. The patient demographics, viral levels, and HCV genotype distribution was similar among
both groups. These investigators did not find a difference in response rates between patients with
cirrhosis vs patients without cirrhosis. These data are in concert with current recommendations that
treatment with combination interferon and ribavirin is indicated for patients with compensated cirrhosis
from HCV.
The Role of Induction Therapy
What is the role of induction therapy in patients infected with HCV? Should patients be initially treated
with higher-dose interferon prior to standard therapy with interferon-alpha 3 million units subcutaneously
3 times/week and oral ribavirin at either 1000 or 1200 mg/day? Will such a strategy result in
improvement of sustained response?
Dr. A.S. Bhatia and colleagues[9] from the Medical College of Virginia evaluated high-dose interferon
therapy in 86 patients and compared the outcome with 95 patients treated with the standard regimen.
Those receiving high-dose therapy received 5 million units of interferon-alpha-2b daily for 1 month,
followed by 5 million units interferon-alpha 2b plus ribavirin 1000-1200 mg/day for 1 month, then 5
million units interferon-alpha 3 times/week plus daily ribavirin for 1 month, and then 9 months of
standard therapy. Approximately one quarter of the patients in both groups were dropped from the study
due to side effects of treatment. At 1 year, there was no difference in virologic response between patients
treated with high-dose induction therapy and those treated with standard therapy. African American
patients, patients with nongenotype 1, and those with an HCV viral load of greater than 2 million copies
of virus/mL prior to treatment were less likely to respond to therapy.
In a similar study, Dr. M. Sjogren and colleagues[10] reported that induction with interferon-alpha 2b 5
million units subcutaneously daily for 4 weeks followed by standard interferon/ribavirin therapy did not
improve treatment response rates over initial standard interferon/ribavirin therapy alone. These data
indicate that induction with high-dose interferon prior to standard treatment will not improve overall
response in HCV therapy.
Side Effects of Combination Therapy
Combination therapy with interferon and ribavirin is associated with some adverse effects. Interferon, for
example, is linked to thyroid dysfunction.
In this setting, Dr. G. Surla and colleagues[11] from New York-Presbyterian Hospital identified 13
patients (8 women, 5 men; average age = 47 years) with thyroid disease following interferon therapy.
Thyroid disease was first recognized 5.3 months following initiation of therapy. Four patients had
hyperthyroidism and 9 patients developed hypothyroidism; 5 of these patients had transient
hyperthyroidism before becoming hypothyroid. Thyroid autoantibodies were present in 5 patients.
Long-term thyroid replacement was required in several of these individuals. Interferon was stopped in
only 3 patients. These findings suggest that therapy with interferon can often be continued despite the
onset of treatment-related hypothyroidism.
How Do You Treat the Patient Who Has Failed Conventional Therapy?
Dr. Nazem Afdhal, from Boston Medical Center,[12] also spoke at this clinical symposium on
management of hepatitis C. He suggested that patients with HCV genotypes 1 and 4 should be treated for
12 months with combination interferon/ribavirin therapy, and that those with genotypes 2 and 3 be
treated with combination therapy for only 6 months. In addition, Dr. Afdhal recommended that those
with advanced fibrosis/cirrhosis be considered for 12 months of therapy regardless of HCV genotype,
and that patients who failed to achieve a sustained response after only 6 months of therapy may be
considered for retreatment with 12 months of therapy. Lastly, he suggested that patients who fail a
12-month combination therapy program should wait for better agents to become available before
considering additional therapy; there is currently no role for routine maintenance therapy outside of
clinical trials. Both Dr. Afdhal and Dr. Fried indicated that combination therapy with pegylated
interferon and ribavirin might be the best future therapy for patients with HCV infection when this
regimen becomes available.
Summary
Chronic infection with HCV is a serious health problem in the United States. Current regimens of
combination therapy with interferon-alpha and ribavirin are more effective than interferon monotherapy.
However, patients with HCV genotype 1 respond more poorly than those with genotypes 2 and 3 to these
regimens. Induction with high-dose interferon prior to initiation of combination therapy does not appear
to convey any added advantage to the standard interferon/ribavirin combination regimen.
References
1. Cumings M, Holtzmuller KC, Smith M, et al. Significance of an elevated alkaline phosphatase
(AP) or and AST/ALT ratio greater than one in hepatitis C (HCV) patients. Am J Gastroenterol.
2000; 95:2509.
2. Brown RS. Hepatocellular carcinoma. Breakfast Session: Liver Cancers: Screening, Diagnosis,
and Treatment. Program and abstracts of the 65th Annual Scientific Meeting of the American
College of Gastroenterology; October 16-18, 2000, New York, NY.
3. Birdi PK, Wustrack S, Balart LA. Combined hepatitis C virus and hepatitis B virus infection and
hepatocellular carcinoma in African Americans. Am J Gastroenterol. 2000;95:2506.
4. Lin OS, Owens DK, Sanders GD, et al. Cost-effectiveness of screening for hepatocellular
carcinoma in patients with cirrhosis secondary to chronic hepatitis C: a decision analysis. Am J
Gastroenterol. 2000;95:2633-2634.
5. Fried M. Symposium: Management of Hepatitis C in the New Millennium. Program and abstracts
of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October
16-18, 2000, New York, NY.
6. Hassanein TI, Monson P, Behling C, et al. Combination therapy results in significant reduction in
transaminase levels in patients with normal pre-treatment transaminase levels. Am J Gastroenterol.
2000;95:2512.
7. Pena R, Kaul V, Suvannashakha A, et al. Patients with hepatitis C infection and normal
transaminases have high sustained response rate to combination therapy. Am J Gastroenterol.
2000;95:2517.
8. Pereyra F, Pena R, Kaul V, et al. Response to combination therapy with interferon and ribavirin in
hepatitis C cirrhotic patients. Am J Gastroenterol. 2000;95:2518.
9. Bhatia AS, Hofmann CM, Sterling RK, et al. A randomized, controlled trial of high dose daily
induction (HDDI) interferon (IFN) plus ribavirin (RVN) versus Rebetron for treatment of chronic
HCV. Am J Gastroenterol. 2000;95:2506.
10. Sjogren MH, Holtzmuller K, Sjogren RW, et al. Failure of induction dosing of interferon to alter
sustained response rates in patients with chronic hepatitis C. Am J Gastroenterol.
2000;95:2519-2520.
11. Surla G, Mahler R, Jacobson IM. Thyroid dysfunction in patients with chronic hepatitis C
treatment with interferon alpha. Am J Gastroenterol. 2000;95:2520.
12. Afdhal N. Approach to the patient who has failed conventional therapy. Symposium: Management
of Hepatitis C in the New Millennium. Program and abstracts of the 65th Annual Scientific
Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY.
Conference Summary - American College of Gastroenterology 65th
Annual Scientific Meeting
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Post Test
Select an answer for each question. A test score of 70% or greater is required for accreditation.
1. The incidence of cancer in a patient with BE is:
a.
Less than 1% per year
b.
1% to 5% per year
c.
5% to 10% per year
d.
More than 10% per year
2. True or false: Normalization of intraesophageal acid exposure is required to successfully
reverse BE with endoscopic techniques.
a.
True
b.
False
3. A 24-year-old woman with perianal Crohn's disease has dramatically improved following 3
infusions with infliximab. Two of her 3 fistulas, including a rectovaginal fistula, have closed and
a third has stopped draining. Her remission should be maintained with:
a.
Infliximab every 8 weeks
b.
Metronidazole
c.
6-mercaptopurine
4. Despite being prescribed a daily dose of 2.0 mg/kg/day of azathioprine for 6 months, a
32-year-old woman with Crohn's disease continues to experience 8-10 bloody bowel movements
per day and abdominal pain before each bowel movement. Her white blood cell count is
5600/mm3. Metabolite levels are checked and show a 6-thioguanine (6-TG) level of 280
pmol/8x108 cells and a 6-methylmercaptopurine (6-MMP) level of 5100 pmol/8x108 cells. Her
azathioprine should be:
a.
Increased to 2.5 mg/kg
b.
Not changed, but she should have 5-aminosalicylic acid added to her regimen
c.
d.
e.
Not changed, but she should have allopurinol added to her regimen
Discontinued as being ineffective
Not changed, but she should be encouraged to be more adherent to medications
5. Which of the following new therapies has been used for ablation of Barrett's esophagus?
a.
Argon plasma coagulation
b.
Endoscopic mucosal resection
c.
Photodynamic therapy
d.
All the above
6. As presented in the material on the new developments in endoscopy, new endoscopic methods
likely to facilitate the detection of abnormal gastrointestinal mucosa include all of the following
EXCEPT:
a.
Optical coherence tomography
b.
Endoscopic confocal microscopy
c.
Flexible endoscopic surgery
d.
Spectroscopy and light-scattering analysis
7. Which of the following scenarios is associated with better response to combination
interferon-alpha/ribavirin therapy?
a.
African American ethnicity
b.
Viral titer greater than 2 million copies/mL
c.
HCV genotype 2
d.
Ethanol consumption
8. True or false: Gender and heredity play a small role in response to drug treatment in IBS
patients.
a.
True
b.
False
9. True or false: The disease burden of IBS is not significantly increased over controls in HMO
populations.
a.
True
b.
False
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54321
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54321
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diseases of the gastrointestinal tract and liver to enhance patient care and improve clinical
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American College of Gastroenterology 65th Annual Scientific Meeting Conference Summaries

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